Data from Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis
Year: 2023
Type: other
Abstract: The classic model of tumor suppression implies that malignant transformation requires full “two-hit” inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a “continuum” model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the “continuum” model of tumor suppression. Cancer Res; 74(22); 6554–64. ©2014 AACR.
Authors: Sophie Couvé, Charline Ladroue, Elodie Laine, Karène Mahtouk, Justine Guégan, Sophie Gad, Hélène Le Jeune, Marion Le Gentil, Gregory Nuel, William Y. Kim, Bernard Lecomte, Jean-Christophe Pagès, Christine Collin, Françoise Lasne, Patrick R. Benusiglio, Brigitte Bressac-de Paillerets, Jean Feunteun, Vladimir Lazar, Anne-Paule Gimenez-Roqueplo, Nathalie M. Mazure, Philippe Dessen, Luba Tchertanov, David R. Mole, William Kaelin, Peter Ratcliffe, Stéphane Richard, Betty Gardie
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4392679864